Photochemical preparation of azlactones and transformation thereof



United States Patent 3,423,302 PHOTOCHEMICAL PREPARATION OF AZLAC- TONES AND TRANSFORMATION THEREOF Harry L. Slates, Florham Park, and Norman L. Wendler, Summit, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Original application Dec. 31, 1963, Ser. No. 334,691, now Patent No. 3,275,648, dated Sept. 27, 1966. Divided and this application Feb. 17, 1966, Ser. No. 553,587 US. Cl. 204-158 Int. Cl. B01j 1/10; C07c 101/42 This is a division of application Ser. No. 334,691, filed Dec. 31, 1963, now Patent No. 3,275,648.

This invention relates to certain azlactones and to the transformation of these azlactones by means of ultraviolet light. More specifically, this invention relates to the racemization of D-2,4-diloweralkyl-4-(3,4 diloweralkanoyloxybenzyl)-azlactones to DL-2,4-di1oweralkyl-4-(3, 4-diloweralkanoyloxybenzyl)-azlactones and to the degradation of D-2,4-diloweralkyl-4(3,4-diloweralkoxybenzyl), (3-loweralkoxy-4-loweralkanoyloxy) and (3-loweralkanoyloxy-4-loweralkoxy)-azlactone, with ultraviolet light, and to processes using these reactions and to new azlactones as compounds.

The discovery that amethyl-3A-dihydroxy phenylalanine (also referred to as u-methyl DOPA) is a potent antihypertensive is a great advance in the treatment of hypertension. This compound can be prepared from various intermediates; such as 3,4-diloweralkoxybenzyl (3- loweralkoxy-4-1oweralkanoyloxybenzyl), (3 loweralkanoyloxy-4-loweralkoxybenzyl), methyl ketones and otloweralkyl N loweralkanoyl 3,4 diloweralkanoyloxyphenylalanines. The two syntheses, which have been used to prepare this amino acid, produce a racemic mixture. The antihypertensive activity, however, resides in the L- form only and resolution of the racemic mixture accumulates large quantities of the inactive D-form, representing large economic waste. Therefore, in order to reduce the eventual cost to the consumer, it is necessary to convert this D-form to the L-form.

We have found that, whereas certain quaternary uamino acids are unafiected by exposure to ultraviolet light, formation of an azlactone derivative of these compounds changes their basic chemistry to such an extent that subsequent exposure to ultraviolet light causes racemization in one group of azlactones and degradation in others. Therefore, we find that when D-a-lower alkyl-3,4-dihydroxy, (3-hydroxy-4-loweralkoxy), (3-loweralkoxy-4- hydroxy) and (3,4-diloweralkoxy) phenylalanine are converted to D-2,4-diloweralkyl-4-(3,4-diloweralkanoyloxybenzyl), (3-loweralkanoyloxy-4-loweralkoxybenzyl), (3- loweralkoxy 4 loweralkanoyloxybenzyl) and (3,4-diloweralkyoxybenzyl)-azlactone respectively, subsequent exposure to ultraviolet light produces racemization of the (3,4-diloweralkanoyloxybenzyl)-azlactone to the corresponding DL-form, and degradation of the (3-loweralkanoyloxy 4 loweralkoxybenzyl), (3 loweralkoxy 4- loweralkanoyloxybenzyl) and (3,4-diloweral-koxybenzyl)- azlactones to the corresponding ketones. Both the ketones and the DL-3,4-diloweralkanoyloxybenzyl-azlactones are highly useful intermediates for the preparation of the racemic amino acids. These racemic amino acids may be prepared by heating the said ketone with ammonium carbonate in a water soluble cyanide salt in an aqueous solution to form a hydantoin derivative. This hydantoin derivative is then hydrolyzed to the said racemic amino acids. The azlactone intermediates may be treated with an aqueous solution of a hydrohalic acid to obtain the said amino acids.

It is an advantage of our invention that (1) certain D-quarternary-u-amino acid compounds can be converted 13 Claims ice to azlactone derivatives which are reactive to ultraviolet light and form intermediates from which the DL-quarternary-a-amino acids can be prepared, and (2) utilization of the D forms of certain -D-quarternary-u-amino acids compounds eliminates economic Waste.

In accordance with this invention certain D-azlactones (which have been prepared by the reaction of certain (D) quarternary amino acids with a lower alkanoic acid anhydride) are converted by means of ultraviolet light to either a DL-azlactone or to a corresponding ketone. The said DL-azlactone is further reacted to form corresponding DL-amino acid derivatives.

In accordance with one aspect of this invention a D-2,4- diloweralkyl-4- (3,4-diloweralkanoyloxybenzyl)- azlactone is exposed to ultraviolet light to form the corresponding DL-azla'ctone. When a D-2,4-diloweralkyl-4-(3,4-diloweralkoxybenzyl), (3 loweralkoxy-4-loweralkanoyloxybenzyl) or (3-loweralkanoyloxy-4-1oweralkoxybenzyl)-azlac tone is exposed to ultraviolet light, racemization does not occur, but rather the compound is degraded to the corresponding a-IOWCI' alkyl-3,4-diloweralkoxybenzyl, (3-loweralkoxy-4-loweralkanoyloxybenzyl) lower alkyl ketone or (3-loweralkanoyloxy-4-loweralkoxybenzyl) lower alkyl ketone respectively. In accordance with another aspect of this invention, a D-a-lower alkyl-3-4,-diloweralkanoyloxyphenylalanine is reacted with a lower alkanoic acid anhydride to form a D-2,4-diloweralkyl-4-(3,4-diloweralkanoyloxybenzyl)-azlactone, exposure of this D-azlactone to ultraviolet light yields the corresponding DL-azlactone and hydrolysis of this DL-azlactone yields a DL-a-loweralkyl-N-lower alkanoyl-3,4-diloweralkanoyloxyphenylalanine. In acordance with a still further aspect of this invention a D-a-lower alkyl-(3,4-diloweralkoxy), (3- loweralkoxy-4-loweralkanoyloxy) or (3-loweralkanoyloxy-4-l0weralkoxy)-phenylalanine reacted with a lower alkanoic acid anhydride to form a D-2,4-diloweralkyl-4- (3,4 diloweralkoxybenzyl), (3 loweralkoxy-4-loweralkanoyloxybenzyl) or (3-loweralkanoyloxy-4-loweralkoxybenzyl)-azlactone respectively and exposure of this D- azlactone to ultraviolet light forms a u-lower alkyl-3,4- diloweralkoxybenzyl, (3,loweralkoxy-4-loweralkanoyloxybenzyl) or (3-loweralkanoyloxy-4-loweralkoxybenzyl)- loweralkyl ketone respectively.

In carrying out the above processes, the starting 3,4- dihydroxy, (3,4-diloweralkoxy), (3-loweralkoxy-4-loweralkanoyloxy) or (3-loweralkanoyloxy-4-loweralkoxy)-alower alkyl phenylalanine may have any a-lower alkyl substituent, as for example, methyl, ethyl, propyl, pentyl and the like (preferably a-methyl) The lower alkoxy may be methoxy, propoxy, amyloxy and the like, preferably methoxy. The lower alkanoyloxy may be acetoxy, propionyloxy and the like, preferably acetoxy.

FLOW SHEET I The processes may be illustrated as follows:

R=lower alkyl, [such as methyl, propyl and amyl (methyl preferred)] R =lower alkanoyloxy, [such as acetoxy and propionyloxy (acetoxy preferred)] R and R lower alkoxy and lower alkanoyloxy, only one of R or R being loweralkanoyloxy at any one time; such as methoxy ethoxy propoxy; amyloxy, acetoxy, propionyloxy and valeryloxy.

R =lower alkyl, [such as methyl and ethyl (methyl preferred)] R =lower alkoxy or lower alkanoyloxy (methoxy or acetoxy preferred) Reaction and conditions Step (1) Reaction of Compound I in an acid binding agent, such as pyridine, with a lower alkanoic acid anhydride such as acetic anhydride, butyric anhydride, pentanoic anhydride and the like, (preferably acetic anhydride) at any suitable temperature (reaction time varies with temperature, room temperature preferred).

(2) Exposing Compound II to ultraviolet light (preferably a solution of Compound 11), until the reaction is substantially complete, (reaction time varies with the intensity of the ultraviolet light).

(3) Reaction of Compound III with water (preferably a solution of acetone and water) at any desired temperature (reaction time varies with temperature, steam bath preferred).

(4) Carried out same as Step 1; starting with Compound V.

(5) Exposing Compound VI to ultraviolet light (preferably a solution of Compound VI), until the reaction is substantially complete, (reaction time varies with the intensity of the ultraviolet light).

The formation of the azlactone, (indicated as Step 1 as well as Step 4), requires the use of an acid binding agent, which will neutralize the acid byproduct formed from the reaction. The acid binding agent may be an organic base; (such as picoline, pyridine, dimethylalanine, quinoline and the like), or a solution of CaCO or Na CO in an inert solvent), (pyridine is preferred). This neutralization is necessary to prevent the conversion of the azlactone back to the amino acid. In addition, this organic base must be one which does not enter into the reaction. When using an acid binding agent such as pyridine, both the pyridine and the anhydride employed will also serve as solvents for the reaction. In the reaction of Step 1, at least 3 moles of anhydride to one mole of Compound I are employed. When less anhydride is used, the reaction will not go to completion. It is preferred to use an excess of acetic anhydride, 3 moles for the reaction and the additional amount as solvent. Any suitable excess may be used which will be effective as a solvent. In addition, for each mole of Compound I at least 3 moles of acid binding agent are employed. When less than 3 moles are used, the reaction (as stated previously) will not go to completion. In the preferred procedure, an excess of pyridine is employed, 3 moles to neutralize the acetic acid formed and the additional amount to act as solvent for the reaction. Here, as in the case of the anhydride, any suitable excess may be used which will be effective as a solvent. The same limitations and preferred conditions exist when Step 4 is employed. In this case only one mole of acid binding agent and anhydride are necessary for the reaction itself and the excess acid binding agent and anhydride are used as solvents.

The reaction of the azlactone with ultraviolet light (1800-3900 Angstrom Units, range of approximately 2900-3200 A. preferred) (as indicated in both Steps 2 and 5) may be run without a solvent, but it is highly preferred to employ an inert solvent. Such solvent must transmit ultraviolet light and be incapable of reacting with the azlactone. Dioxane, ethers and some hydrocarbons may therefore be used as solvents, although dioxane is the solvent of choice. The reaction time appears to be a function of the intensity of the ultraviolet light employed, and can therefore be varied by changing the intensity of the ultraviolet light. In addition, the reaction may be run at any convenient temperature, however room temperature is preferred. The effect of reaction, and therefore, the time required for substantial completion can be determined by following the loss of optical activity.

Hydrolysis of the DL-azlactone (Step 3) may be accomplished with water, but it is preferred to use a solution of an inert water soluble organic solvent and water (such as acetone-H O). This mixture will enhance the solubility of the DL-azlactone and lead to more effective reaction. Any desired amount of water acetone may be used, which will affect solution and allow complete hydrolysis.

In the case of Step 5, the reaction of the D-azlactone with ultraviolet light produces the degradated ketone directly, no water being necessary, although water has been used after exposure of the D-azlactone to ultraviolet light with the same results.

The following examples are given by way of illustration.

EXAMPLE 1 D -,2,4-dimethyl-4-(3,4-diacetoxybenzyl)-azlactone A solution of 10 grams of D(+)-a-methyl-3,4-dihydroxyphenylalanine in ml. of pyridine and 50 ml. of acetic anhydride is allowed to stand at room temperature overnight. The solvents are removed in vacuo and the residue is distilled at 160-170 at 0.05 mm. in a short path still. There is obtained 9 grams of D(+)-2,4-dimethyl-4-(3,4-diaoetoxybenzyl)-azlactone as a colorless viscous oil [a];; +67.

When the above procedure is followed using propionic anhydride and pentanoic anhydride in place of acetic anhydride in the above example, there are obtained D(+)-2-ethyl-4-methyl-4 (3,4 dipropionyloxybenzylJ- azlactone and D(+)-2-butyl-4-methyl 4 (3,4-divaleryloxybenzyl) -azlactone respectively.

When the above procedure is followed using D(+)-"apropyl-3,4-dihydroxy-phenylalanine and D(+)-a-pentyl- 3,4-dihydroxyphenylalanine in place of D(+)-a-methyl- 3,4-dihydroxyphenylalanine in the above example, there are obtained D(+)-2-methyl-4-propyl-4-(3,4-diacetoxybenzyl)-azlactone and D(+ )-2'-methyl-4-pentyl-4-(3,4-diacetoxybenzyl -azlactone respectively.

. EXAMPLE 2 DL-2,4-dimethyl-4- 3 ,4-diacetoxybenzyl) -azlactone A solution of 600 mg. of D(+)-2,4-dimethyl-4-(3,4- diacetoxybenzyl)-azlactone in 20 ml. of dioxone is irradiated f or 6 days in a quartz flask with a high pressure mercury arc ultraviolet lamp. The solvent is removed in vacuo to yield crude DL-2,4-dimethyl-4-(3,4-diacetoxybenzyl)-azlactone.

When the above procedure is followed using D )-2-ethyl-4-methyl-4- 3 ,4-dipropionyloxybenzyl azlactone,

D )-2-butyl-4-methyl-4- 3 ,4-divaleryloxybenzyl azlactone,

D )-2-methyl-4-propyl-4- 3,4-diacetoxybenzyl) azlactone,

D -2-methyl-4-pentyl-4- 3,4-diacetoxybenzyl azlactone 1 in place of D(+)-2,4-dimethyl-4-(3,4-diacetoxybenzyl)- azlactone, in the above example, there are obtained the corresponding DL-azlactones.

EXAMPLE 3 DL-a-methyl-3,4-dihydroxyphenylalanine triacetate The crude DL-2,4-dimethyl-'4-(3,4-diacetoxybenzyl)-azlactone from Example 2 is taken up in aqueous acetone and warmedon a steam bath for ,one hour. The solid prod- I duct is separated and recrystallized from acetone-hexane. There is obtained a-methyl-3,4-dihydroxyphenylalanine triacetate, M.P. 176-179 [041 +49.4, showing 20% racemization. H

When the above procedure is followed using DL-2-ethyl-4-methyl-4-'( 3,4-dipropionyloxybenzyl azlactone, DL-2-butyl-4-methyl-4- (3,4-divaleryloxybenzyl) azlactone, DL-2-methyl-4-propyl-4- 3,4-diacetoxybenzyl azlactone and DL-2-methyl-4-pentyl-4-(3,4-diacetoxybenzyl) azlactone, obtained from Example 2, in place of DL-2,4-dimethyl-4-(3,4-diacetoxybenzyl)-azlactone in the above example, there are obtained DL-a-methyl-3',4 dihydroxyphenylalanine tripropionate, DL-a-methyl-3,4-dihydroxyphenylalanine tripentanoate, DL-a-propyl-3,4-dihydroxyphenylalanine triacetate and DL-a-pentyl-3,4-dihydroxyphenylalanine triacetate respectively.

overnight. The solvents are removed in vacuo and the residue is crystallized from ether-hexane to yield 3.5

6 grams of D(+)-2,4dirnethyl-4-(3,4-dimethoxybenzyl)- azlactone, M.P. 9192 [11] =-+-84.2.

When the above procedure is followed using D(+)-apropyl-3,4-dimethoxyphenylalanine, D( +)-a-pentyl 3,4- dimethoxyphenylalanine, D -a-methyl-3,4-dipropoxyphenylalanine and D(+)-a-methyl-3,4-dipentoxyphenylalanine in place of D(+-w-methyl-3,4-dimethoxyphenylalanine in the above example there are obtained D(+)-4- propyl-Z-methyl 4 (3,4 dimethoxybenzyl) azlactone, D(+)-4-pentyl-2-methyl-4-(3,4-dimethoxybenzyl) azlactone, D(+) 2,4-dimethyl-4-(3,4-dipropoxybenzyl)-azlactone and D( +)-2,4-dirnethyl-4-( 3,4-dipentoxybenzyl) -azlactone respectively.

When the above procedure is followed using propionic anhydride and pentanoic anhydride in place of acetic anhydride in the above example, there are obtainedD(+)- 2 ethyl 4-methyl-(3,4-dimethoxybenzyl)-azlactone and D(+) 2 butyl 4 methyl-4-(3,4-dimethoxybenzyl)- azlactone respectively.

EXAMPLE 5 3,4-dimethoxybenzyl methyl ketone A solution of 1.1 grams of D(|)-2,4-dimethyl-4-(3,4- dimethoxybenzyl)-azlactone in 40 mls. of dioxane in a quartz flask is irradiated for 90 hours at room temperature with a high pressure mercury arc ultraviolet lamp equipped with a heat filter. (At this point the solution has lost 85% of its optical rotation.) The reaction mixture is concentrated in vacuo to a pale yellow oil. The oil is dissolved in 60 mls. of ether, washed with saturated potassium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to yield 0.65 gram of essen tially pure 3,4-dimethoxybenzyl methyl ketone.

When the above procedure is followed using D(+)-2,4- dimethyl-4-(3,4-dipropoxybenzyl) azlactone, D(+)-2,4- dimethyl 4 (3,4-dipentoxybenzyl) azlactone, D(+)-2- methyl-4propyl-4-(3,4-dimethoxybenzyl) azlactone, and D(+) 2 methyl 4 pentyl-4-(3,4-dimethoxybenzyl)- azlactone in place of D( )-2,4-dimethyl-4-(3,4-dimethoxybenzyl) azlactone in the above example there are obtained 3,4-dipropoxybenzyl methyl ketone, 3,4-dipentoxybenzyl methyl ketone, 3,4-dimethoxybenzyl propyl ketone and 3,4-dimethoxy benzyl pentyl ketone respectively.

EXAMPLE 6 D( -2,4-dimethyl-4-(3-methoxy-4-acetoxybenzyl)- azlactone A solution of 4 grams of D(+)-a-methyl-(3-methoxy- 4-hydroxy) phenylalanine, 20 mls. of pyridine and 30 mls. of acetic anhydride is allowed to stand at room temperature overnight. The solvents are removed in vacuo and the residue is distilled through a short path column to yield D(+) 2,4 dimethyl-4-(3-rnethoxy-4-acetoxybenzyl)-azlactone.

When the above procedure is followed using D(+)-umethyl-(3-hydroxy-4-methoxy)-phenylalanine in place of D(+) a-methyl-(3-methoxy-4-hydroxy)-phenylalanine, in the above example, there is obtained D(+)-2,4-dimethyl-4- 3-acetoxy-4-methoxybenzyl -azlactone.

Similarly, when the above procedure is followed using D( cc propyl-(3-methoxy-4-hydroxy)-phenylalanine, D(-|-) t-amyl-(3-methoxy-4-hydroxy)-phenylalanine in place of D(+yet-methyl-(3-methoxy-4-hydroxy)-phenylalanine there are obtained D(+)-2-methyl-4-propyl-4- (3 methoxy 4-acetoxybenzyl)-azlactone and D(+)-2- methyl 4 amyl 4 (3 methoxy 4 acetoxybenzyl)- azlactone respectively.

Similarly, when the above procedure is followed u'sing propionic anhydride and pentanoic anhydride in place of acetic anhydride there are obtained D(+)-2-ethyl-4- methyl 4 (3-meth0xy-4-propionyloxybenzyl)-azlactone and D( -2-butyl-4-methyl-4- 3-methoxy-4-valeryloxy)- azlactone respectively.

EXAMPLE 7 3-methoxy-4-acetoxybenzyl-methyl ketone A solution of 1.1 grams of D(+)-2,4-dimethyl-4-(3- rnethoxy-4-acetoxybenzyl)azlactone in 40 ml. of dioxane in a quartz flask is irradiated for 90 hours at room temperature with a high pressure mercury arc ultraviolet lamp equipped with a heat filter. The reaction mixture is concentrated in vacuum; the residue is dissolved in 60 ml. of ether, washed with saturated potassium carbonate solution, dried over magnesium sulfate and concentrated in vacuo to yield 3-methoxy-4-acetoxybenzyl-methyl ketone.

When the above procedure is followed using D -2,4-dimethyl-4- (3 -propoxy-4-aeetoxybenzyl azlactone,

D )-2,4-dimethyl-4- 3 -pentoxy-4-acetoxybenzyl azlactone,

D )-2,4-dimethyl-4- 3-acetoxy-4-propoxybenzyl azlactone,

D( -2,4-dimethyl-4- (3 -acetoxy-4-pentoxybenzyl) azlactone,

D -2-ethyl-4-methyl-4- 3-methoxy-4- propionyloxyb enzyl -azl actone,

D -2-butyl-4-methyl-4- 3 -methoxy-4- valeryloxybenzyl) -azlactone,

D( )-2-ethyl-4-methyl-4-(3-propionyloxy-4- methoxybenzyl -azlactone,

D -2-butyl-4-methyl-4- 3-valeryloxy-4- methoxybenzyl) -azlactone,

in place of l D -2,4-dimethyl-4- 3-methoxy-4-acetoxybenzyl azlactone there are obtained (3 -propoxy-4-aeetoxybenzyl -methyl ketone, (3-pentoxy-4-acetoxybenzyl -methylketone,

( 3-acetoxy-4- pro poxyb enzyl -methylketone,

(3 -acetoxy-4-pentoxybenzyl) -methylketone,

(3 -methoxy-4-propionyloxybenzyl -methylketone, (3 -methoxy-4-valeryloxybenzyl -methylketone,

( 3-propionyloxy-4-methoxybenzyl) -methylketone, (3 -valeryloxy-4-methoxybenzyl -methylketone,

respectivley.

We claim:

1. A process for converting a (D)-2,4-diloweralkyl-4- (3,4-diloweralkanoyloxybenzyl)-azlactone to a DL-2,4- diloweralkyl 4-(3,4-diloweralkanoyloxybenzy)-azlactone which comprises the step of: (a) exposing said D- azlactone to ultraviolet light, to form the desired DL- azlactone.

2. A process for converting a D-2,4-diloweralkyl-4- (3,4-diloweralkanoyloxybenzyl)-azlactone to a DL-2,4 diloweralkyl-4-(3,4-diloweralkanoyloxybenzyl) azlactone which compirses the step of: (a) exposing a solution of, said D-azlactone in an inert solvent to ultraviolet light to form the desired DL-azlactone.

3. A process of converting D-2,4-dimethyl-4,(3,4- diacetoxybenzyl)-azlactone to DL-2,4-dimethyl-4-(3,4- diacetoxybenzyl)-azlactone which comprises the step of (a) exposing a solution of, said D-azlactone in dioxane to ultraviolet light to form the desired DL-azlactone.

4. A process for converting a D-a-loweralkyl-3,4- dihydroxyphenylalanine to a DL-a-loWeralkyl-N-lower alkanoyl 3,4 diloweralkanoyloxy phenylalanine which comprises, in combination, the steps of:

(a) admixing a solution of said D-3,4-dihydroxyphenylalanine in an acid binding agent with a lower alkanoic acid anhydride to form a (D)-2,4-diloweralkyl-4-(3,4-diloweralkanoyloxyhenzyl)-azlactone;

(b) exposing said (D)-azlactone to ultraviolet light to form a DL-2,4-diloweralkyl-4-(3,4-diloweralkanoy1- oxybenzyl)-azlactone; and

(c) admixing said DL-azlactone with Water to produce the desired DL phenylalanine.

5. A process for converting a D-a-loweralkyl-3,4- dihydroxyphenylalanine to a DLa-loweralkyl-N-loweralkanoyl-3,4-diloweralkanoyloxyphenyalanine which comprises, in combination, the steps of:

(a) admixing a solution of said D-3,4-dihydroxyphenylalanine in pyridine with a lower alkanoic acid anhydride to form a D-2,4-diloweralkyl-4-(3,4-diloweralkanoyloxybenzyl) -azlactone:

(b) epoxing a solution of said D-azlactone, in an inert solvent, to ultraviolet light to form a DL-2,4-diloweralkyl 4-(3,4-diloweralkanoyloxybenzyl)-azlactone; and

(c) admixing said DL-azlactone with water to produce the desired DL-phenylalanine.

6. A process for converting D-a-methyl-3,4-dihydroxyphenylalanine to DL-a-methyl-N-acetyl 3,4 diacetoxyphenylalanine which comprises, in combination, the steps of:

(a) admixing a solution of said D-3,4-dihydroxy phenylalanine in pyridine with acetic anhydride to form D-2,4-dimethyl-4-(3,4-diacetoxybenzyl) azlactone;

(b) exposing a solution of said D-azlactone in dioxane to ultraviolet light to form DL-2,4-dimethyl-4-(3,4 diacetoxybenzyl)-azlactone; and

(c) admixing said DL-azlactone with water to produce the desired DL-phenylalanine.

7. A process for converting a compound selected from the group consisting of D-2,4-diloweralkyl-4-(3-loweralkoxy-4-loweralkanoyloxybenzyl)-azlactone, D 2,4 di- 1oweralkyl-4-(3-loweralkanoyloxy 4 loweralkoxybenzyl)-azlactone and D-2,4-dilower alkyl-4-(3,4-diloweralkoxybenZyD-azlactone to a compound selected from the group consisting of (3-loweralkoxy-4-loweralkanoyloxybenzyl)-lower alkyl ketone, (3-loweralkanoyloxy-4 loWeralkoxybenzyD-lower alkyl ketone and 3,4-diloweralkoxybenzyl lower alkyl ketone which comprises the step of exposing said D-azlactone to ultraviolet light to form the desired lower alkyl ketone.

8. A process for converting a compound selected from the group consisting of D-2,4-diloweralkyl-4-(3-loweralkoxy 4 loweralkanoyloxybenzyl)-azlactone, D-2,4-diloweralkyl-4- 3-loweralkanoyloxy-4 loweralkoxybenzyl azlactone and D 2,4 diloweralkyl 4-(3,4-diloweralkoxybenzyl)-azlactone to a compound selected from the group consisting of (3-loweralkoxy-4-loweralkanoyloxybenzyl)- loweralkyl ketone, (3-loweralkanoyloxy-4 loweralkoxybenzyl)-lower alkyl ketone and 3,4-diloweralkoxybenzyl lower alkyl ketone which comprises the step of exposing a solution of said D-azlactone, in an inert solvent, to ultraviolet light, to form the desired lower alkyl ketone.

9. A process for converting a compound selected from the group consisting of D-2,4-dimethyl-4-(3-methoxy-4- acetoxybenzyl)-azlactone, D-2,4-dimethyl4-( 3 acetoxy- 4-methoxybenzyl)-azlactone and D-2,4-dimethyl-4 (3,4- dimethoxybenzyl)-azlactone to a compound selected from the group consisting of (3-methoxy-4-acetoxybenzyl)- methyl ketone, (3 acetoxy 4 methoxybenzyl) methyl ketone and 3,4-dimethoxy-benzy1 methyl ketone which comprises the step of exposing a solution of said D-azlactone, in dioxane, to ultraviolet light, to form the desired methyl ketone.

10. A process for converting a compound selected from the group consisting of D-a-loweralkyl-(Zi-loweralkoxy-4-hydroxy)phenylalanine, 4 a lower alkyl-(3- hydroxy-4-loweralkoxy) phenylalanine and D a lower alkyl-3,4-diloweralkoxy-phenylalanine to a compound selected from the group consisting of (3-1oweralkoXy-4- loweralkanoyloxybenzyl)-lower alkyl ketone, (3-loweralkanoyloxy-4-loweralkoxybenzyl)-lower alkyl ketone and 3,4-diloweralkoxybenzyl lower alkyl ketone which comprises, in combination, the steps of:

(a) admixing a solution of said D-3,4-disubstituted phenylalanine in an acid binding agent with a lower alkanoic acid anhydride to form a D-2,4-dilower a1kyl-4-(3,4-disubstituted benzyl)-azlactone; and

(b) exposing said D-azlactone to ultraviolet light, to

form the desired lower alkyl ketone.

11. A process for converting a compound selected from the group consisting of D-u-loweralkyl-(3-loweralkoxy-4-hydroxy) phenylalanine, (D)-a-loweralkyl-(3- hydroxy-4-loweralkoxy)-phenylalanine and D 0t loweralkyl-(3,4-diloweralkoxy)phenylalanine to a compound selected from the group consisting of (3-loweralkoxy-4- loweralkanoyloxybenzyl)-lower alkyl ketone, (3-loweralkanoyloxy-4-loweralkoxybenzyl)-lower alkyl ketone and 3,4-diloweralkoxybenzyl lower alkyl ketone which comprises, in combination, the steps of:

(a) admixing a solution of said D-3,4-disubstituted phenylalanine in pyridine with a lower alkanoic acid anhydride to form a D-2,4-dilower alkyl-4-(3-disubstitutedbenzyl -azlactone; and

(b) exposing a solution of said D-azlactone, in an inert solvent, to ultraviolet light, to form the desired lower alkyl ketone.

12. A process for converting a compound selected from the group consisting of D-a-methy1-(3-methoxy-4- hydroxy)-phenylalanine, D-a-methyl-(3hydroxy 4 methoxy)-phenylalanine and D-a-methyl 3,4 dimethoxyphenylalanine to a compound selected from the group consisting of (3-methoxy-4-acetoxybenzyl)-rnethylketone, (3-acetoxy-4-methoxybenzyl)-methy1ketone and 3,4 di- 10 methoxybenzyl methyl ketone which comprises, in combination, the steps of:

(a) admixing a solution of said D-3,4-disubstitutedphenylalanine in pyridine with acetic anhydride to form D-2,4-dimethyl-4 (3,4 disubstitutedbenzyl)- azlactone; and

(b) exposing a solution of said D-azlactone, in dioxane, to ultraviolet light, to form the desired methyl ketone.

13. A process for converting D-a-methyl-3,4-dihydroxyphenylalanine to DL-2,4-dimethyl 4 (3,4 diacetoxybenzyl)-azlactone which comprises, in combination, the steps of:

(a) admixing a solution of said D-dihydroxyphenylalanine in pyridine with acetic anhydride to form D- 2,4-dimethyl-4-(3,4-diacetoxybenzyl) azlactone; and

(b) exposing a solution of said D-azlactone, in dioxane, to ultraviolet light, to form the desired DL-azlactone.

HOWARD S. WILLIAMS, Primary Examiner.

US. Cl. X.R. 2605 18 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3r423:302 Dated January 21, 1969 I ventor) H. L. Slates and Norman L. Wendler It is certified that error appears in the above-identified patent and that: said Letters Patent are hereby corrected as shown below:

Column 2, Line 41 3, should read "3-";

Column 4, Line 71 Delete [,1 after D(+) Column 6, Line 7 D(+- should read "D(+) --a-";

Column 8, Line 11 Delete [epoxing] and add "exposing"; Column 8, Line 67 4-ashould read "Dc1";

Column 9, Line 18 (3-disubstitutedbenzyl) should read "(3,4-disubstitutedbenzyl)".

SIGNED AND SEALED wees-m (su mm! B. mm, an E4 dMFletcher Ir iflsioner of Patents momm- 

1. A APROCESS FOR CONVERTING A (D)-2,4-DILOWERALKYL-4(3,4-DILOWERALKANOYLOXYBENZYL)-AZLACTONE TO A DL-2-4DILOWERALKYL - 4-(3,4-DILOWERALKANOYLOXYBENZY)-AZLACTONE WHICH COMPRISES THE STEP OF: (A) EXPOSING SAID DAZLACTONE TO ULTRAVIOLET LIGHT, TO FORM THE DESIRED DLAZLACTONE. 